Axillary radiation with surgery in breast cancer patients often leads to lymphedema, which affects nearly 400,000 women in the United States. Lymphedema is disfiguring, painful and forms a nidus for infection. As current treatments provide little relief for many patients, it is critical to develop methods to prevent and reverse the formation of lymphedema. The use of lymphangiogenic growth factors to spur lymphatic growth and reverse lymphedema has been advocated. However, in cancer patients this strategy may facilitate the further spread of cancer cells. To avoid this complication, we focus on lymphedema prevention in this Pathway to Independence Award. While information on the radiosensitivity of many tissues is available, the effects of radiation on lymphatic vessels have been largely unreported. In this proposal we will study the radiosensitivity of lymphatic endothelial cells and their cellular and moecular response to radiation (Aim 1, Mentored Phase). We will then alter lymphatic endothelial cell radiosensitivity through exposure to growth factors or genetic manipulation of growth factor signaling (Aim 2, Independent Phase). We will complement these studies by measuring the radiosensitivity of normal and proliferating lymphatic vessels in vivo (Aim 3, Independent Phase). Finally, we will prevent radiation induced damage of lymphangiogenic vessels by administering inhibitors of lymphatic growth factor receptors (Aim 3, Independent Phase). The ultimate goal of this project is to identify strategies to protect lymphatic vessels from radiation-induced damage in order to prevent lymphedema in patients. I will complete the Mentored Phase at Massachusetts General Hospital under the guidance of Dr. Brian Seed (Mentor) and Dr. Kathy Held (Co-mentor). I will use this Mentored Phase to strengthen my knowledge of molecular biology and biochemistry, and radiobiology, the respective expertises of my mentors. During this period I will have the resources of the E.L. Steele Laboratory and those of my mentors available, as well as many educational and training opportunities at Harvard University, Harvard Medical School and Massachusetts Institute of Technology. My mentors are committed to the development of my career and will help my transition into a successful independent academic researcher. I will secure an independent faculty position for the Independent Period of this Award. I will also vigorously pursue other funding opportunities to support additional research activities in lymphatic biology and cancer metastasis during this period. By the end of the term of this Award, I intend to have established a strong independent research program. Relevance: Nearly 400,000 breast cancer patients in the United States develop lymphedema after axillary radiation. Lymphedema treatments are generally designed to control swelling and minimize the pain associated with lymphedema, but these treatments are only marginally effective. Understanding the response of lymphatic vessels to radiation will help design strategies to prevent lymphedema formation in breast cancer patients.